Epidermal Nonpeptidergic Nerves Modulate Cutaneous Immunity

表皮非肽能神经调节皮肤免疫

基本信息

批准号：
10440275
负责人：
Kathryn Marie Albers
金额：
$ 55.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440275
关键词：
Ablation Acute Afferent Neurons Agonist Allergic Disease Automobile Driving Candida albicans Cell Degranulation Cell physiology Cells Chronic Contact hypersensitivity Croton Cutaneous Data Dendritic Cells Dendritic cell activation Dermal Dermis Development Diphtheria Toxin Epidermis Event G-Protein-Coupled Receptors Genetic Goals Haptens Host Defense IL17 gene Immune Immune response Immunity Immunologic Tests Immunosuppression Individual Infection Infectious Skin Diseases Inflammation Inflammatory Innate Immune Response Interleukin-17 Interruption Irritants Lasers Link Mechanoreceptors Mediating Modeling Mus Nerve Neurogenic Inflammation Neuroimmune Neurons Nociceptors Oils Organ Pain Pathogenesis Pathway interactions Phenotype Primates Production Pruritus Resistance Sensory Skin Somatostatin Staphylococcus aureus Stimulus TRPV1 gene Testing Th2 Cells Touch sensation Work afferent nerve antagonist base cutaneous sensory neurons diphtheria toxin receptor extracellular gain of function immune function in vivo loss of function mast cell optogenetics pain sensation pathogen response single-cell RNA sequencing transcriptomics

项目摘要

Abstract The skin is a highly innervated organ and contains numerous sensory afferent neurons that respond to a diverse array of stimuli including touch, pruritogens (inducing itch) and noxious agents (inducing pain). There are also many skin-resident immune cells including dendritic cells and mast cells that make direct contact with sensory neurons. It has very recently become appreciated that cutaneous sensory neurons and skin-resident innate immune cells work synergistically to initiate local inflammation and host defense. We have previously shown that TRPV1+ neurons that sense pain are necessary and sufficient for cutaneous innate Type-17 inflammation and host defense against C. albicans. Thus, a neuron subset associated with painful stimuli is necessary and sufficient to drive a Type-17 immune response which is the optimal immune response against extracellular pathogens that can cause painful stimuli. We now propose to test the immunologic potential of nonpeptidergic sensory neurons are that can be divided based on single cell RNAseq into at least 3 subsets: NP1, NP2, and NP3. The overall goal of this proposal is to understand the unique contribution of individual subsets of nonpeptidergic sensory neurons to the modulation of skin immunity. Exploring this neuro- immune interaction will better define the cellular circuits driving inflammation and allow for the use of agonists/antagonists that target neuron subsets in order to modulate specific types of cutaneous immune responses without global immunosuppression. Specifically, we hypothesize that NP1 sensory nerves function to suppress mast cell activity. We further hypothesize that the NP2 and NP3 subsets that communicate itch sensation in response to pruritogens also participate in the development of Type-2 immune responses analogous to TRPV1+ neurons and Type-17 immune responses. The potential to modulate Th2 and mast cell function makes these pathways potential key for allergic disease pathogenesis.

抽象的皮肤是一个高度支配的器官，包含许多感官传入神经元响应各种刺激，包括触摸，瘙痒（刺激）和有害的刺激特工（引起疼痛）。也有许多包括树突状细胞在内的皮肤居民免疫细胞和与感觉神经元直接接触的肥大细胞。它最近成为感谢皮肤的感觉神经元和皮肤居住的先天免疫细胞起作用协同启动当地炎症和宿主防御。我们以前已经表明 trpv1+神经元，即感觉疼痛是必需的，足以使皮肤先天类型17 炎症和对白色念珠菌的宿主防御。因此，与与之相关的神经元子集疼痛刺激是必要的，足以驱动17型免疫反应，这是对可能引起疼痛刺激的细胞外病原体的最佳免疫反应。我们现在建议测试非肽性感觉神经元的免疫学潜力是可以基于单细胞RNASEQ将至少3个子集进行分配：NP1，NP2和NP3。这该提案的总体目标是了解单个子集的独特贡献非肽性感觉神经元调节皮肤免疫。探索这个神经 - 免疫相互作用将更好地定义驱动炎症的细胞电路，并允许使用针对神经元子集的激动剂/拮抗剂，以调节特定类型的类型皮肤免疫反应没有全球免疫抑制。具体来说，我们假设 NP1感觉神经功能抑制肥大细胞活性。我们进一步假设 NP2和NP3子集也可以响应瘙痒剂传达瘙痒感参与与TRPV1+神经元类似的2型免疫反应的发展和 17型免疫反应。调节Th2和肥大细胞功能的潜力使这些过敏性疾病发病机理的途径潜在的关键。